{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T01:32:34Z","timestamp":1787621554437,"version":"build-2736575974"},"reference-count":63,"publisher":"Bioscientifica","issue":"2","content-domain":{"domain":["journals.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,11,1]]},"abstract":"<jats:p>Non-alcoholic fatty liver disease (NAFLD) is the fastest-growing cause of liver-associated death globally. Whole-body knockout (KO) of Na+\/H+ exchanger 1 (NHE1, SLC9A1) was previously proposed to protect against high-fat diet-induced liver damage; however, mechanistic insight was lacking. The aim of the present work was to address this question in vitro to determine how NHE1, specifically in hepatocytes, impacts lipid overload-induced inflammation, fibrosis, and hepatocyte\u2013hepatic stellate cell (HSC) crosstalk. We induced palmitate (PA)-based steatosis in AML12 and HepG2 hepatocytes; manipulated NHE1 activity pharmacologically and by CRISPR\/Cas9-mediated KO and overexpression; and measured intracellular pH (pHi), steatosis-associated inflammatory and fibrotic mediators, and cell death. PA treatment increased NHE1 mRNA levels but modestly reduced NHE1 protein expression and hepatocyte pHi. NHE1 KO in hepatocytes did not alter lipid droplet accumulation but reduced inflammatory signaling (p38 MAPK activity), lipotoxicity (4-HNE accumulation), and apoptosis (poly-ADP-ribose-polymerase-1 (PARP) cleavage). Conditioned medium from PA-treated hepatocytes increased the expression of NHE1 and of the fibrosis regulator tissue inhibitor of matrix metalloproteinases-2 in LX-2 HSCs, in a manner abolished by NHE1 KO in hepatocytes. We conclude that NHE1 is regulated in NAFLD in vitro and contributes to the ensuing damage by aggravating hepatocyte injury and stimulating hepatocyte\u2013HSC crosstalk.<\/jats:p>","DOI":"10.1530\/joe-24-0099","type":"journal-article","created":{"date-parts":[[2024,8,16]],"date-time":"2024-08-16T07:48:20Z","timestamp":1723794500000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-5","source":"Crossref","is-referenced-by-count":5,"title":["NHE1 regulation in NAFLD\n                    <i>in vitro<\/i>\n                    contributes to hepatocyte injury and HSC crosstalk"],"prefix":"10.1530","volume":"263","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6595-3086","authenticated-orcid":true,"given":"Lise M","family":"Sj\u00f8gaard-Frich","sequence":"first","affiliation":[{"name":"Section for Cell Biology and Physiology 1","department":["Department of Biology, Faculty of Science, University of Copenhagen, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morten S\u00f8lling","family":"Henriksen","sequence":"additional","affiliation":[{"name":"Section for Cell Biology and Physiology 1","department":["Department of Biology, Faculty of Science, University of Copenhagen, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi Min","family":"Lam","sequence":"additional","affiliation":[{"name":"Section for Cell Biology and Physiology 1","department":["Department of Biology, Faculty of Science, University of Copenhagen, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frida Jolande","family":"Birkbak","sequence":"additional","affiliation":[{"name":"Section for Cell Biology and Physiology 1","department":["Department of Biology, Faculty of Science, University of Copenhagen, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominika","family":"Czaplinska","sequence":"additional","affiliation":[{"name":"Section for Cell Biology and Physiology 1","department":["Department of Biology, Faculty of Science, University of Copenhagen, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mette","family":"Flinck","sequence":"additional","affiliation":[{"name":"Section for Cell Biology and Physiology 1","department":["Department of Biology, Faculty of Science, University of Copenhagen, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3044-7714","authenticated-orcid":true,"given":"Stine Falsig","family":"Pedersen","sequence":"additional","affiliation":[{"name":"Section for Cell Biology and Physiology 1","department":["Department of Biology, Faculty of Science, University of Copenhagen, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","published-online":{"date-parts":[[2024,8,16]]},"reference":[{"key":"2026070806112047400_bib1","doi-asserted-by":"crossref","first-page":"2362","DOI":"10.1038\/s41467-020-16092-0","article-title":"Hepatocyte mitochondria-derived danger signals directly activate hepatic stellate cells and drive progression of liver fibrosis","volume":"11","author":"An","year":"2020","journal-title":"Nature Communications"},{"key":"2026070806112047400_bib2","doi-asserted-by":"crossref","first-page":"2529","DOI":"10.1002\/ijc.31276","article-title":"The net acid extruders NHE1, NBCn1 and MCT4 promote mammary tumor growth through distinct but overlapping mechanisms","volume":"142","author":"Andersen","year":"2018","journal-title":"International Journal of Cancer"},{"key":"2026070806112047400_bib3","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1042\/CS20030326","article-title":"Increase in long-chain polyunsaturated fatty acid n - 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